From The Editor | April 26, 2024

What To Expect From An FDA Inspection


By Dan Schell, Chief Editor, Clinical Leader

Patrick Stone
"When I see patient safety compromised, I am a bear," says Patrick Stone.

By all accounts, Patrick Stone is a nice guy. Until he’s not.

What flicks that switch is when this former FDA consumer safety officer/investigator uncovers something during a clinical trial site audit that risks patient safety. “When I see patient safety compromised, I am a bear. I'm a polar bear. And I don't stop,” says Stone, who for the past 13 years has focused on BIMO (bioresearch monitoring) quality assurance and regulatory consulting. I met Stone at this year’s inaugural Save Our Sites conference where he spoke about, among many things, what to expect when you find out an FDA inspector is coming to audit your site.

During our interview, and in his conference presentations, he stressed that inspectors are not your enemy, and their findings are not personal. Every inspector is following the objective FDA guidelines; no suggestions or recommendations are subjective. Still, he’s seen many tears shed during his years of auditing sites. “Sometimes research coordinators feel like we are picking on them personally or picking on their project,” Stone says. “But it’s really not like that. We are simply there to ensure patient safety, data integrity, and investigational product accountability.”

“Big Emotions” From Site Audits

One common issue he’s seen that elicits “big emotions” from site staff is the identification of patients who should or should not have been enrolled in a study based on I/E criteria. Sometimes, the site will be surprised this was identified, saying the monitor never caught anything during routine visits. But a finding like this could indicate the monitors weren’t sufficiently trained or are spread too thin by a CRO, not having enough time to complete their work. Maybe they weren’t catching primary or secondary endpoint data gaps or adverse events that should have been listed as serious adverse events. Or, maybe they missed a 24-hour reporting period for an adverse event, or they didn’t have their first site visit until months after a study started. A lot can happen during those early days of a study. Even site staff may not fully understand all the little nuances of the study.

Stone says that about a third of his current clients are proactive, asking him to do a gap analysis before a mock FDA inspection. The latter, he says, can be morale breaking depending upon how seasoned the company is with inspections.  “I’ve worked with some clients whose upper management has gone into disarray after a mock inspection, upset about how their timeline is going to be pushed back or the fact that they don’t have the money to address the issues I uncover. But if I find out they are hiding safety data — and I’ve seen this — then I try to stress to them that progressing to an FDA application without remediation of my findings is going to be a waste of time and money. As an FDA inspector, if I had to present a company with a 483 with a lot of observations, they usually could foresee a warning letter being the next step, and that’s when people would break down.”

Misconceptions & Disconnects

In a Q&A at the SOS conference, I remember some of the questions people had for Stone concerned simply how to act around an inspector auditing a site. Can you offer them bottled water? Does anyone have to be in the room with them? Who can interact with them? What can you ask them?

Stone confirmed during our interview that there are a lot of common misconceptions about these audits and the whole process, and that’s understandable. After all, the FDA doesn't generally go multiple times to a site; most often, these are first-time audits of sites with no prior history with the agency.

If it's a directed for-cause inspection for a specific project or protocol, the inspector is really focused on the PI, not the overall site itself. Stone says there are always misconceptions about what the inspector requires, especially in terms of how much time they need with the PI. “At first, I want at least 20 minutes with them so I can kind of gauge just general items,” Stone says. “After I've looked at the regulatory records, the investigator site files, training records, etc., I’ll have more specific questions for them. I try to determine their oversight and how much they actually participated, because sometimes the sub investigators or the CRCs do most everything.” He says, depending on the clinic, the trial participants are the PI’s patients, so they’re the standard-of-care patient and they're the research subjects. In those cases, the PIs are a lot more aware and involved than, say, a larger site that has multiple studies happening concurrently.

If, for example, sub-investigators are writing up AE or SAE reports, is the PI aware of those documents and events? Do they go over them with some sort of safety committee or data-monitoring committee? How about accountability for IP, protocol deviations, or even screen failures? When faced with these kinds of project-specific questions, Stone says he’s usually met with quizzical looks from the PI, who often look to the CRC. “But I'm looking at the PI saying, ‘You are overseeing all of it, regardless of who's doing what. It all falls to you.’ So, I have to remind them about the 1572 and who signed the protocol, the investigator brochure, and the project’s contract. Typically, that’s the PI, so they understand delegation of authority, but they don't understand oversight of delegation. And when the PI is presiding over, say, eight or nine studies, there’s often a disconnect. They don't necessarily realize that if you're doing eight or nine studies, you need to be overseeing eight or nine studies.”

It Pays — Not Costs — To Be Proactive

If you’re looking for a site to emulate regarding how to best run a trial, if it’s a Phase 1, Stone says go to the UK. “They’re inspected beyond belief over there. Those inspectors are busting out the white gloves and looking at everything there is, even the nutritional value of the food provided to patients.” He did give kudos to a U.S.-based site he recently visited that was a purpose-built Phase 1 unit with impeccable facilities, including a sports-bar-like lunchroom complete with top-of-the-line video and arcade games.   

Not surprisingly, Stone touts the advantages of being proactive, but not in the way you may think, i.e., scheduling mock inspections. Instead, he talks a lot about the importance of sponsors investing in quality control. “Quality control is more important than QA because it looks at 100% of data, every single entry. Quality assurance is looking at the high risk, most critical and important aspects of that QC, but it doesn't look at everything.”

When he worked for the FDA, Stone says they would normally schedule a week to do an inspection, with many of them taking 3-4 days. As a consultant, he usually gets 1-2 days to complete an audit.

A lot has changed in the industry since Stone left the FDA in 2011. For example, he says these days he consults more and more for cell & gene companies. But his focus as an auditor still remains the same. As he says in his book, Bubble Gum Badge: An FDA His-Story, “I am for public safety and protection, so if that is what you work for, we work together. … FDA business is not personal; it is a professional environment of producers and regulators.”